title: Contribution of ABCC4-mediated gastric transport to the absorption and efficacy of dasatinib.
abstract: OBJECTIVE
  Several oral multikinase inhibitors are known to interact in vitro with the human ATP-binding cassette transporter ABCC4 (MRP4), but the in vivo relevance of this interaction remains poorly understood. We hypothesized that host ABCC4 activity may influence the pharmacokinetic profile of dasatinib and subsequently affect its antitumor properties.
  
  
  METHODS
  Transport of dasatinib was studied in cells transfected with human ABCC4 or the ortholog mouse transporter, Abcc4. Pharmacokinetic studies were done in wild-type and Abcc4-null mice. The influence of Abcc4 deficiency on dasatinib efficacy was evaluated in a model of Ph(+) acute lymphoblastic leukemia by injection of luciferase-positive, p185(BCR-ABL)-expressing Arf(-/-) pre-B cells.
  
  
  RESULTS
  Dasatinib accumulation was significantly changed in cells overexpressing ABCC4 or Abcc4 compared with control cells (P < 0.001). Deficiency of Abcc4 in vivo was associated with a 1.75-fold decrease in systemic exposure to oral dasatinib, but had no influence on the pharmacokinetics of intravenous dasatinib. Abcc4 was found to be highly expressed in the stomach, and dasatinib efflux from isolated mouse stomachs ex vivo was impaired by Abcc4 deficiency (P < 0.01), without any detectable changes in gastric pH. Abcc4-null mice receiving dasatinib had an increase in leukemic burden, based on bioluminescence imaging, and decreased overall survival compared with wild-type mice (P = 0.048).
  
  
  CONCLUSIONS
  This study suggests that Abcc4 in the stomach facilitates the oral absorption of dasatinib, and it possibly plays a similar role for other orally administered substrates, such as acetylsalicylic acid. This phenomenon also provides a mechanistic explanation for the malabsorption of certain drugs following gastric resection.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Furmanski
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Shuiying
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Fujita
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Lie
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Alice A
authors.initials: AA
authors.lastname: Gibson
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Janke
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Williams
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: John D
authors.initials: JD
authors.lastname: Schuetz
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
mesh_terms: D000042:Absorption; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D001692:Biological Transport; D000069439:Dasatinib; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D013844:Thiazoles / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D000069439:Dasatinib; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; C073492:ABCC4 protein, human